Post-traumatic stress disorder (PTSD) is a common and debilitating neuropsychiatric disorder in which an acute fear response to a traumatic event does not abate. This failure to recover from trauma is thought to be due at least in part to a deficit in learning not to fear situations and stimuli previously associated with the trauma. Thus, PTSD has been conceptualized as a disorder of 'fear conditioning' that involves a hyperresponsivity of neurons in brain regions mediating fear expression and a hyporesponsivity of neurons in brain regions mediating fear extinction. Moreover, converging evidence suggests that neurotransmitter alterations relate to these changes in neuron excitability, including alterations in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The proposed study will apply proton magnetic resonance spectroscopy (1H-MRS) methods to test hypotheses that PTSD is associated with altered GABA in two key brain areas: the ventromedial prefrontal cortex (VMPFC) and anterior insular cortex. We will also employ a well-validated fear conditioning paradigm to examine the hypothesis that VMPFC neurochemistry is associated with fear extinction deficits in PTSD. We will recruit 93 subjects comprised of 31 PTSD subjects, 31 trauma- exposed controls, and 31 healthy controls with no trauma history. Subjects will undergo single voxel high-field 1H-MRS using MEGAPRESS sequences that are optimized for detection and quantification of GABA, and have yielded encouraging preliminary data in these two brain regions. We will examine GABA levels in relation to PTSD diagnosis and symptoms, and in relation to behavioral indices of fear extinction recall and anxiety sensitivity. This will allow us to examine whether regional brain GABA is a marker of clinical and behavioral phenotypes of PTSD. Future research directions will include examination of whether GABA alterations in PTSD are sensitive to pharmacological treatment, and examination of their diagnostic specificity. Indeed, it is likely that GABA alterations represent biomarkers of behavioral phenotypes that are not only found in PTSD but also related psychiatric disorders. In this way, the goals of this research are relevant to priorities delineated in the NIMH strategic plan and RDoC initiative, particularly the identification of biobehavioral markers that may lead to the development of a biologically-valid psychiatric nosology. PUBLIC HEALTH RELEVANCE: The proposed study may provide the first direct, in vivo evidence that altered levels of the brain chemical GABA are markers of persistent clinical symptoms and fear responses in post- traumatic stress disorder (PTSD). In the short-term, our findings will improve our understanding of brain chemistry in PTSD and of how brain chemistry relates to certain maladaptive behaviors that cause impairment in patients. In the longer term this research may help understand how current treatments affect brain chemistry, and ultimately may lead to better diagnosis and treatment of PTSD and related disorders.